Glucokinase (hereinafter described as GK) belongs to the hexokinase family and catalyzes phosphorylation of glucose incorporated in cells such as pancreatic beta cells or hepatocytes. GK in the liver and GK in pancreatic beta cells differ from each other in terms of the sequence of N-terminal 15 amino acids due to the difference in splicing but are enzymatically identical. GK has a high affinity to glucose S0.5 of about 10 mM and is not inhibited by the product, glucose 6-phosphate. Therefore, its reaction rate sensitively responds to physiological changes of blood glucose levels. GK in pancreatic beta cells modulates glucose-dependent insulin secretion, while GK in the liver modulates the glycolytic pathway or glycogenesis, so that blood glucose levels are maintained and controlled. Therefore, GK is assumed to function as a glucose sensor to maintain homeostasis of blood glucose levels (see Non-Patent Document 1).
Genetically engineered mice and gene mutations discovered in humans support a hypothesis that GK functions as an in vivo glucose sensor. GK homozygous mice have been died of hyperglycemia immediately after birth, and heterozygous mice have been observed to have hyperglycemia and impaired glucose tolerance (see Non-Patent Document 2). In contrast, GK overexpressed mice have been confirmed to have hypoglycemia (see Non-Patent Document 3). Moreover, in human MODY2 (maturity onset diabetes of the young), in which GK gene mutation is observed, diabetes develops from his youth (see Non-Patent Document 4). These gene mutations have been confirmed to reduce GK activity. In contrast, families have been reported having gene mutations to enhance GK activity (see Non-Patent Document 5). These gene mutations have been observed to enhance affinity of GK to glucose and cause symptoms of fasting hypoglycemia associated with elevated blood insulin concentrations.
In this way, GK has been shown to function as a glucose sensor in mammals including humans.
Substances to increase GK activity (hereinafter described as GK activating substances) may improve hyperglycemia by increasing glucose metabolism and glycogenesis in the liver and/or glucose-induced insulin secretion from pancreatic beta cells. It can also expected that improvement of hyperglycemia leads to treatment and prevention of chronic diabetic complications such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis and to treatment and prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension and metabolic syndrome. Therefore, compounds to increase the function of GK are expected to be effective therapeutic agents for diabetes.
On the other hand, GK has been reported to be expressed not only in the pancreas and liver but also in the feeding center and to have an important function in the antifeeding effect by glucose (see Non-Patent Document 6). Accordingly, GK activating substances may act on the feeding center and have an antifeeding effect and can be expected not only as therapeutic agents for diabetes but also as therapeutic agents for obesity.
Certain propionamide compounds, picolinamide compounds, benzamide compounds and benzimidazole compounds have conventionally been reported as GK activating substances, but the compounds of the present invention have not been disclosed (see Patent Document 1, 2, 3 and 4). 2-Pyridone compounds structurally similar to the compounds of the present invention have also been reported, but the compounds of the present invention have not been disclosed; such compounds differ from the compounds of the present invention in that they are not described for pharmaceutical applications and are intended to provide a process for synthesizing 2-pyridone compounds (see Non-Patent Document 7). Moreover, 2-pyridone compounds have been reported as therapeutic agents for diabetes, but they differ from the compounds of the present invention in terms of the structure, for example, the substituent at the 3-position of pyridone (see Patent Document 5). Further, certain acylurea compounds that can have a pseudocyclic structure have been reported as GK activating substances, but they are noncyclic compounds and differ from the compounds of the present invention (see Patent Document 6).